Ion channels responsive to L-glutamate, comprise an extremely important class of neural cell receptors. These ligand-gated ion channels regulate both monovalent and divalent cation gradients, and mediate fast synaptic responses. The finding that glutamate receptors underlie the molecular basis of learning and memory emphasizes their critical role in the normal physiology of the central nervous system. Glutamate receptors also play a central role in neuronal death following excessive glutamate release associated with trauma or chronic illness. In this case the loss of the receptor's ability to properly regulate calcium gradients is believed to underlie the cytotoxicity. The glutamate receptor subunit, GluR-6, is a component of glutamate channels that are defined by the agonist, kainate. This subunit also undergoes and RNA processing event known as RNA editing, which determines the calcium permeability properties of ion channels containing GluR-6. The aim of this proposal is to characterize the patterns of GluR-6 editing in different regions of the mouse brain and to identify the cis-active and trans-active molecular signals which regulate the editing of GluR-6 transcripts. GluR-6 genes derived from a mouse genomic library will be used to determine the cis-active elements which control RNA editing in vivo, and the trans-active components involved in GluR-6 editing will be studied using cell extracts. These experiments will yield important insights into the regulation of a metabolic pathway believed to be intimately linked to both normal and aberrant physiological conditions of the nervous system.